title: Interaction of Shiga toxin with the A-domains and multimers of von Willebrand Factor.
abstract: Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli causes diarrhea-associated hemolytic-uremic syndrome (DHUS), a severe renal thrombotic microangiopathy. We investigated the interaction between Stx and von Willebrand Factor (VWF), a multimeric plasma glycoprotein that mediates platelet adhesion, activation, and aggregation. Stx bound to ultra-large VWF (ULVWF) secreted from and anchored to stimulated human umbilical vein endothelial cells, as well as to immobilized VWF-rich human umbilical vein endothelial cell supernatant. This Stx binding was localized to the A1 and A2 domain of VWF monomeric subunits and reduced the rate of ADAMTS-13-mediated cleavage of the Tyr(1605)-Met(1606) peptide bond in the A2 domain. Stx-VWF interaction and the associated delay in ADAMTS-13-mediated cleavage of VWF may contribute to the pathophysiology of DHUS.
authors.affiliation: From the Department of Bioengineering, Rice University, Houston, Texas 77005.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Lo
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Turner
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cruz
authors.forename: Joel
authors.initials: J
authors.lastname: Moake
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D054324:Enterohemorrhagic Escherichia coli / Q000378:metabolism; D004927:Escherichia coli Infections / Q000378:metabolism / Q000473:pathology; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D022622:Shiga Toxin 1 / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D022622:Shiga Toxin 1; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: Adamts13; Hemolytic Uremia; Platelets; Shiga Toxin; Thrombosis; Toxins; Von Willebrand Factor